Colorectal cancer (CRC) is the second most common cause of cancer deaths in humans, and about 5% of the US population will develop CRC in their life times. Overall, CRC growth, progression, and metastasis involve a gradual accumulation of genetic and epigenetic changes over a period of years. One approach to control CRC growth and metastasis could be its prevention by phytochemicals, which inhibit one or more neoplastic events and reduce the risk of cancer. One such phytochemical is silibinin, the major active constituent in a widely consumed dietary supplement, milk thistle extract. It is noteworthy that silibinin is devoid of any toxicity in animal studies as well as in humans. In fact, it is clinically used as hepatoprotective agent in humans. Recently, we observed that silibinin significantly inhibits growth, causes G1/G2-M arrest, and induces apoptosis in human colon carcinoma HT29 cells, and that silibinin feeding significantly inhibits HT29 tumor xenograft growth in nude mice. Recent studies have also shown that silymarin (a crude form of silibinin) feeding prevents azoxymethane (AOM) and 1,2-dimethylhydrazine-induced colon carcinogenesis in rat model. Together, based on these studies, we hypothesize that silibinin is a novel colon cancer preventive agent, and targets cell cycle progression and cell survival signaling leading to its antiproliferative and apoptotic efficacy against CRC. Our specific aims are to: I) further assess and establish silibinin efficacy in animal CRC models, II) define and establish molecular targets of silibinin effects on cell cycle progression, III) define effect of silibinin on cell survival/antiapoptotic signaling, and IV) examine and define effect of silibinin on apoptosis regulators. We anticipate that proposed studies, will identify silibinin as a mechanism-based agent for the prevention, growth control and therapy of CRC, and will establish its in vivo efficacy in pre-clinical carcinogenic, genetic and xenograft CRC models. As a practical and translational approach, the long-range goal of these studies would be to define and establish the usefulness of silibinin for the prevention and therapy of human CRC. Accordingly, we anticipate that completion of proposed studies in this grant would position us for a pilot clinical trial with silibinin in CRC patients.